Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas
| Autor: | Hong Zheng, Robert P. Mecham, R. Edward Watts, Keith M. Rich, Chaitan Khosla, Tracy C. Holmes, Liya Yuan, Enrique Izaguirre, Thomas J. Broekelmann |
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| Rok vydání: | 2010 |
| Předmět: |
Radiation-Sensitizing Agents
Cancer Research Programmed cell death Tissue transglutaminase Blotting Western Fluorescent Antibody Technique Motility Antineoplastic Agents Apoptosis Article Mice Cell Movement Cell Line Tumor In Situ Nick-End Labeling Animals Humans PI3K/AKT/mTOR pathway biology Kinase Isoxazoles Cell biology Neurology Oncology biology.protein Neurology (clinical) Signal transduction Glioblastoma Intracellular Signal Transduction |
| Zdroj: | Journal of Neuro-Oncology. 103:207-219 |
| ISSN: | 1573-7373 0167-594X |
| Popis: | Glioblastomas display variable phenotypes that include increased drug-resistance associated with enhanced migratory and anti-apoptotic characteristics. These shared characteristics contribute to failure of clinical treatment regimens. Identification of novel compounds that promote cell death and impair cellular motility is a logical strategy to develop more effective clinical protocols. We recently described the ability of the small molecule, KCC009, a tissue transglutaminase (TG2) inhibitor, to sensitize glioblastoma cells to chemotherapy. In the current study, we synthesized a series of related compounds that show variable ability to promote cell death and impair motility in glioblastomas, irrespective of their ability to inhibit TG2. Each compound has a 3-bromo-4,5-dihydroisoxazole component that presumably reacts with nucleophilic cysteine thiol residues in the active sites of proteins that have an affinity to the small molecule. Our studies focused on the effects of the compound, ERW1227B. Treatment of glioblastoma cells with ERW1227B was associated with both down-regulation of the PI-3 kinase/Akt pathway, which enhanced cell death; as well as disruption of focal adhesive complexes and intracellular actin fibers, which impaired cellular mobility. Bioassays as well as time-lapse photography of glioblastoma cells treated with ERW1227B showed cell death and rapid loss of cellular motility. Mice studies with in vivo glioblastoma models demonstrated the ability of ERW1227B to sensitize tumor cells to cell death after treatment with either chemotherapy or radiation. The above findings identify ERW1227B as a potential novel therapeutic agent in the treatment of glioblastomas. |
| Databáze: | OpenAIRE |
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